Early increase of VEGF‐A is associated with resolution of ventilator‐associated pneumonia: Clinical and experimental evidence

• Published in: Respirology (Carlton, Vic.) Vic.), 2018-10, Vol.23 (10), p.942-949
• Main Authors: Strouvalis, Ioannis, Routsi, Christina, Adamopoulou, Maria, Raftogiannis, Maria, Renieris, George, Orfanos, Stylianos E., Kotanidou, Anastasia, Sabracos, Labros, Giamarellos‐Bourboulis, Evangelos J.
• Format: Article
• Language: English
• Subjects: Alveoli; Animal models; Animals; Anti-Bacterial Agents - therapeutic use; APACHE; Bevacizumab; Biomarkers - blood; Bronchoalveolar Lavage Fluid - chemistry; Bronchus; Clarithromycin - therapeutic use; Double-Blind Method; Humans; IL-1β; Interferon-gamma - metabolism; Interleukin-1beta - metabolism; Lungs; Mice; Monoclonal antibodies; outcome; Peroxidase; Peroxidase - metabolism; Pneumonia; Pneumonia, Bacterial - metabolism; Pneumonia, Bacterial - microbiology; Pneumonia, Ventilator-Associated - blood; Pneumonia, Ventilator-Associated - drug therapy; Prospective Studies; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas Infections - metabolism; Respiratory diseases; Time Factors; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - blood; Vascular Endothelial Growth Factor A - metabolism; Ventilators; γ-Interferon
• ISSN: 1323-7799; 1440-1843
• DOI: 10.1111/resp.13320

ABSTRACT Background and objective The role of vascular endothelial growth factor (VEGF)‐A in the resolution of ventilator‐associated pneumonia (VAP) was investigated in clinical and mouse pneumonia models. Methods VEGF‐A was measured for seven consecutive days by an immunosorbent assay in sera of 82 patients with VAP and changes from baseline were correlated with the resolution of VAP. Experimental animals were challenged intratracheally with Pseudomonas aeruginosa. Mouse bronchoalveolar lavage (BAL) samples and segments of lung tissue were obtained at 24, 48 and 124 h after bacterial challenge. Levels of VEGF‐A, tumour Necrosis Factor alpha (TNF‐α), interleukin (IL)‐1β, interferon‐gamma (IFNγ) and myeloperoxidase (MPO) activity were measured in these samples. Results VAP resolved in 36.1% of patients with a less than 45% increase of VEGF‐A on day 5 compared to 65.2% of patients with a more than 45% increase (P = 0.014). This was also accompanied by an earlier resolution of VAP (log‐rank: 7.99; P = 0.005) and it was not pathogen‐specific. The increase of VEGF‐A was an independent variable associated with VAP resolution in forward logistic regression analysis where Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were included as independent variables. VEGF‐A in mouse BAL and lung tissue increased significantly at 124 h but not with the other mediators. In mice pre‐treated with bevacizumab, VEGF‐A concentrations decreased while TNF‐α and MPO significantly increased. Conclusion In patients, an association between increased levels of circulating VEGF‐A and VAP resolution was observed. The mouse study suggests that elevated VEGF‐A levels may be associated with lung inflammation resolution. Clinical trial registration: NCT00297674 at www.clinicaltrials.gov A significant increase in human blood vascular endothelial growth factor (VEGF)‐A is associated with early resolution of ventilator‐associated pneumonia (VAP); this was an independent predictor of resolution despite disease severity. Experimental chronic lung infection by Pseudomonas aeruginosa in mice led to increased VEGF‐A concentrations in the lung and a reciprocal decrease of pro‐inflammatory cytokines and myeloperoxidase activity.